The purpose of this project is to better understand how drugs affect the mechanisms of the ionic conductance in membranes which are voltage dependent and excitable. These studies involve the use of the squid giant axon. In particular, we have studied the structure-activity-relationship of the use-dependent drug, yohimbine. Our studies indicate that the stereo-isomeric configuration of the reactive groups are inconsequential to this use-dependent effect. However, this use-dependent effect is dependent upon the quaternary ammonium at position 4 on the yohimbine molecule. The nitrogen at this site of the active form of yohimbine is positively charged, indicating that a negative site of the receptor is involved in this use-dependent effect.